Published: 7 June 2019

Publications

NSAIDs and cardiovascular risk

Prescriber Update 40(2): 26-28
June 2019

Key Messages

  • All NSAIDs, including both traditional and COX-2 selective NSAIDs, increase the risk of a cardiovascular adverse event.
  • It is not possible to differentiate or rank NSAIDs by their cardiovascular risk.
  • Cardiovascular adverse events occur with both short-term and long-term use.
  • Use NSAIDs at the lowest effective dose for the shortest time possible.

Background

The Medicines Adverse Reactions Committee (MARC) reviewed the cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs) at the 177th meeting on 14 March 2019.

Recent cardiovascular safety studies

Since the MARC previously discussed the cardiovascular safety of diclofenac in 2013 1 and ibuprofen in 20152, several new studies on the cardiovascular safety of NSAIDs have been published.

Medsafe presented a report on the recent literature to the MARC at the 177th meeting on March 20193. These studies include two key clinical trials4,5, and two large observational studies using healthcare databases6,7. In addition, there have been two meta-analyses of older studies8,9, a Danish healthcare registry study examining the risk of out-of-hospital cardiac arrest with NSAIDs10, and a case-control study nested in a cohort derived from European electronic healthcare databases that examines the risk of hospital admission for heart failure exacerbation in new users of NSAIDs11.

The MARC reviewed these studies and concluded that it is currently not possible to differentiate NSAIDs by their individual cardiovascular risk profiles12. All NSAIDs increase cardiovascular risk, and the risk is increased with both short-term and long-term use.

Clinical implications

  • Avoid using all NSAIDs in patients with established cardiovascular disease, and in those with significant risk factors.
  • If required, use NSAIDs at the lowest effective dose for the shortest duration possible.
  • Inform patients that NSAIDs increase the risk of cardiovascular adverse events, even in those without a history of cardiovascular disease, and about the symptoms and signs to look out for.

Mechanism of action

NSAIDs reduce inflammation by inhibiting the production of cyclo-oxygenase (COX), an important enzyme in prostaglandin synthesis. There are two major forms of the COX enzyme: COX-1 and COX-2. While COX-1 is present in most tissues all the time, COX-2 is expressed in response to inflammation. Both forms catalyse the conversion of arachidonic acid, via intermediates, to thromboxane A2 (pro-thrombotic) and prostacyclin (anti-thrombotic).

COX-selectivity is relative, not absolute

NSAIDs are generally divided into non-selective traditional NSAIDs and selective COX-2 inhibitors. Comparisons are often made between selective COX-2 inhibitors and traditional NSAIDs in clinical studies. However, there is much overlap between the two classes in the degree of COX-2 inhibition. For example, among the traditional NSAIDs, indomethacin and naproxen are relatively COX-1 selective, while diclofenac and meloxicam are relatively COX-2 selective. Furthermore, celecoxib (a selective COX-2 inhibitor) and diclofenac (a traditional NSAID) have a similar degree of COX-2 selectivity13.

The balance between COX-1 and COX-2 inhibition can change during the dose interval, depending on the potency and plasma half-life of the NSAID. For diclofenac, COX-1 inhibition drops off as the plasma concentration falls during the dose interval, leaving COX-2 inhibition relatively unopposed. In contrast, for both ibuprofen and naproxen, COX-1 inhibition exceeds COX-2 inhibition throughout the dose interval14,15.

When COX-2 is inhibited relative to COX-1, the pro-thrombotic/antithrombotic balance on the endothelial surface shifts in favour of thrombosis, increasing the risk of cardiovascular thrombotic adverse events. Relative COX selectivity also influences the gastrointestinal adverse event profile of individual NSAIDs16.

NSAID cardiotoxicity is multifactorial

In addition to potential pro-thrombotic effects, other factors contributing to the cardiovascular toxicity of NSAIDs include blood pressure elevation, reduced renal perfusion, fluid retention, and exacerbation of heart failure13,17,18.

References
  1. Medsafe. 2013. NSAIDs and risk of cardiovascular events. Prescriber Update 34(3): 26. URL: https://medsafe.govt.nz/profs/PUArticles/Sept2013NSAIDS.htm (accessed 8 May 2019).
  2. Medsafe. 2015. Ibuprofen and cardiovascular risk. Prescriber Update 36(3): 42. URL: https://www.medsafe.govt.nz/profs/PUArticles/Sep2015/Ibuprofen&Cardiovascular.htm (accessed 9 May 2019).
  3. Medsafe. 2019. NSAIDs and cardiovascular risk: an update. Presented at the 177th Medicines Adverse Reaction Committee Meeting 14 March 2019. URL: https://medsafe.govt.nz/committees/MARC/reports/177-3.2.2%20NSAIDs%20-%20an%20update%20on%20CVD%20risk.pdf (accessed 14 May 2019).
  4. Nissen SE, Yeomans ND, Solomon DH, et al. 2016. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. New England Journal of Medicine 375(26): 2519–29. DOI: 10.1056/NEJMoa1611593 (accessed 14 January 2019).
  5. MacDonald TM, Hawkey CJ, Ford I, et al. 2017. Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT). European Heart Journal 38(23): 1843–50. DOI: 10.1093/eurheartj/ehw387 (accessed 1 February 2019).
  6. Schmidt M, Sørensen HT, Pedersen L. 2018. Diclofenac use and cardiovascular risks: series of nationwide cohort studies. BMJ 362: k3426. URL: https://www.bmj.com/content/362/bmj.k3426 (accessed 1 February 2019).
  7. Bally M, Dendukuri N, Rich B, et al. 2017. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ 357: j1909. URL: https://www.bmj.com/content/357/bmj.j1909 (accessed 8 February 2019).
  8. Gunter BR, Butler KA, Wallace RL, et al. 2017. Non-steroidal anti-inflammatory drug-induced cardiovascular adverse events: a meta-analysis. Journal of Clinical Pharmacy and Therapeutics 42(1): 27–8. DOI: 10.1111/jcpt.12484 (accessed 1 February 2019).
  9. Ungprasert P, Srivali N, Kittanamongkolchai W. 2015. Non-steroidal anti-inflammatory drugs and risk of heart failure exacerbation: A systematic review and meta-analysis. European Journal of Internal Medicine 26(9): 685–90. DOI: http://dx.doi.org/10.1016/j.ejim.2015.09.012 (accessed 21 February 2019).
  10. Sondergaard KB, Weeke P, Wissenberg M, et al. 2017. Non-steroidal anti-inflammatory drug use is associated with increased risk of out-of-hospital cardiac arrest: a nationwide case-time-control study. European Heart Journal – Cardiovascular Pharmacotherapy 3(2): 100–107. DOI: 10.1093/ehjcvp/pvw041 (accessed 1 February 2019).
  11. Arfè A, Scotti L, Varas-Lorenza C, et al. 2016. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ 354: i4857. URL: https://www.bmj.com/content/354/bmj.i4857 (accessed 16 February 2019).
  12. Medsafe. 2019. Minutes of the 177th Medicines Adverse Reaction Committee Meeting 14 March 2019. URL: https://www.medsafe.govt.nz/profs/adverse/Minutes177.htm (accessed 29 April 2019).
  13. Schmidt M, Lamberts M, Schjerning Olsen A-M, et al. 2016. Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology. European Heart Journal – Cardiovascular Pharmacotherapy 2: 108–18. DOI:10.1093/ehjcvp/pvv054 (accessed 8 February 2019).
  14. Grosser T, Yu Y, Fitzgerald GA. 2010. Emotion recollected in tranquility: lessons learned from the COX-2 saga. Annual Review of Medicine 61: 17–33. DOI: 10.1146/annurev-med-011209-153129 (accessed 11 February 2019).
  15. Schwartz JI, Dallob AL, Larson PJ, et al. 2008. Comparative inhibitory activity of etoricoxib, celecoxib, and diclofenac on COX-2 versus COX-1 in healthy subjects. Journal of Clinical Pharmacology 48(6): 745–54. DOI: 10.1177/0091270008317590 (accessed 16 February 2019).
  16. Medsafe. 2010. Reducing the risk of GI reactions with NSAIDs and/or COX-2 inhibitors. Prescriber Update 31(4): 32. URL: https://medsafe.govt.nz/profs/PUArticles/ReducingGIReactionRiskwith%20NSAIDsAndCox2.htm (accessed 14 May 2019).
  17. Novartis New Zealand Ltd. Voltaren 50 mg enteric coated tablet New Zealand Data Sheet 27 March 2018. URL: www.medsafe.govt.nz/profs/Datasheet/v/voltarentab.pdf (accessed 14 February 2019).
  18. Pfizer New Zealand Ltd. 25 October, 2018. Celecoxib Pfizer 100 mg, 200 mg capsules New Zealand Data Sheet 25 October 2018. URL: www.medsafe.govt.nz/profs/Datasheet/c/Celebrexcap.pdf (accessed 14 February 2019).
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